重新发明PARP1抑制:利用虚拟筛选和分子动力学模拟来识别抗癌治疗的重新用途药物。

IF 2.4 3区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
Mohammad Khalid, Mohammed H Alqarni, Ahmed I Foudah, Mishary Saad Al Oraby
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引用次数: 0

摘要

聚(adp -核糖)聚合酶1 (PARP1)是一种核蛋白,在DNA修复中起关键作用,并已成为癌症治疗的一个有希望的靶点。重新利用现有的fda批准的药物来抑制PARP1,为药物发现提供了一条加速的途径。在这里,我们提出了一种综合的方法来重新利用药物来抑制PARP1,同时利用基于结构的虚拟筛选和分子动力学(MD)模拟的综合方法。首先,筛选了来自DrugBank的3648种fda批准的药物,以确定能够与PARP1结合的潜在候选药物。我们的研究揭示了PARP1活性位点内具有良好结合谱和稳定相互作用的药物分子子集。尼罗替尼(Nilotinib)是根据其药物特征选择的,并进行了详细的分析,包括相互作用研究和500 ns全原子MD模拟。通过整合多种计算方法,我们为尼洛替尼的选择提供了一个合理的框架,在进一步的实验中证明了它的PARP1结合特性和治疗开发的潜力。这项研究强调了计算方法在加速药物再利用方面的力量,为确定parp1相关疾病的新治疗方案提供了有效的策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Reinventing PARP1 inhibition: harnessing virtual screening and molecular dynamics simulations to identify repurposed drugs for anticancer therapeutics.

Poly (ADP-ribose) polymerase 1 (PARP1) is a nuclear protein that plays a pivotal role in DNA repair and has emerged as a promising target for cancer therapy. Repurposing existing FDA-approved drugs for PARP1 inhibition offers an accelerated route to drug discovery. Here, we present an integrated approach to drug repurposing for PARP1 inhibition while utilizing an integrated approach involving structure-based virtual screening and molecular dynamics (MD) simulations. First, a curated library of 3648 FDA-approved drugs from DrugBank was screened to identify potential candidates capable of binding to the PARP1. Our study reveals a subset of drug molecules with favorable binding profiles and stable interactions within the PARP1 active site. The standout candidate, Nilotinib, was selected based on its drug profile and subjected to a detailed analysis, including interaction studies and 500 ns all-atom MD simulations. By integrating multiple computational approaches, we provide a rational framework for the selection of Nilotinib, demonstrating its PARP1 binding features and potential for therapeutic development after further experimentation. This study highlights the power of computational methods in accelerating drug repurposing efforts, offering an efficient strategy for identifying novel therapeutic options for PARP1-associated diseases.

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来源期刊
Journal of Biomolecular Structure & Dynamics
Journal of Biomolecular Structure & Dynamics 生物-生化与分子生物学
CiteScore
8.90
自引率
9.10%
发文量
597
审稿时长
2 months
期刊介绍: The Journal of Biomolecular Structure and Dynamics welcomes manuscripts on biological structure, dynamics, interactions and expression. The Journal is one of the leading publications in high end computational science, atomic structural biology, bioinformatics, virtual drug design, genomics and biological networks.
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